Preparation of 1-alkyl-1,4-dihydro-7-substituted-4-oxo-1,8-naphthyridine-3-carboxylic acids via the 3-hydroxymethyl analogs

ABSTRACT

Process of reacting 1,4-dihydro-4-oxo-7-Q-1,8-naphthyridine (I) with a hydroxymethylating agent to produce 1,4-dihydro-3hydroxymethyl-4-oxo-7-Q-1,8-naphthyridine II, reacting II with a lower-alkylating agent to produce 1-(lower-alkyl)-1,4-dihydro-3hydroxymethyl-4-oxo-7-Q-1,8-naphthyridine (III), and oxidizing III to produce 1-(lower-alkyl)-1,4-dihydro-4-oxo-7-Q-1,8naphthyridine-3-carboxylic acid (IV), where Q is lower-alkyl, lower-alkanoyloxymethyl, 4(or 3)-pyridyl or 4(or 3)-pyridyl having one or two lower-alkyl substituents. The final products (IV) are known antibacterial agents, as are the corresponding 7hydroxymethyl compounds which are prepared by hydrolysis of the final products where Q is 7-(lower-alkanoyloxymethyl). A further process comprises reacting 1,4-dihydro-7-methyl-4-oxo-1,8naphthyridine-8-oxide (V) with a hydroxymethylating agent to produce 1,4-dihydro-3-hydroxymethyl-7-methyl-4-oxo-1,8naphthyridine-8-oxide (VI) and oxidizing VI to produce 3-carboxy1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-8-oxide (VII). The 8-oxide (VII) is converted in three steps via the 7-(loweralkanoyloxymethyl) compound to 1-ethyl-1,4-dihydro-7hydroxymethyl-4-oxo-1,8-naphthyridine-3-carboxylic acid.

ilrnted States Patent [1 1 [111 3,869,464 Lesher et a1. Mar. 4, 1975 1 1PREPARATION OF 57 ABSTRACT 1'ALKYLlA'DIHYDROJ'SUBSTITUTEDA Process ofreacting 1,4-dih .dro-4-oxo-7-Q-1.8- OXU-l18-NAPHTHYRIDINE-3-CARBOXYLICnaphthyridine (I) with a hydroxymethylating agent to ACIDS VIA THE3-HYDROXYMETHYL produce 1,4-dihydro-3-hydroxymethy1-4-oxo-7-Q-1,8-ANALOGS naphthyridine II, reacting II with a lower-alkylating [75]Inventors: George Y. Lesher, Schodack; Monte to produce I'Uower- 11). Guett, E t G b h, f as men us both 0)-1,4-dihydro-3-hydroXymethy1-4-oxo7-Q-1,8- naphthyridine (III), andoxidizing III. to produce [73] Asstgneez Sterling Drug Inc., New York,NY. 1 (1 wer-a1kyl)-l,4-dihydro- [22] Filed. 26, 19734-oXo-7-Q-1,8-naphthyridine-3-car'boxy1ic acid (IV), where Q 15lower-alkyl, lower-alkanoyloxymethyl, 4(or 1 1 PP .1 335,734 3)-pyridy1or 4(or 3)-pyridy1 having one or two 1oweralky1 substituents. The finalproducts (IV) are known [52] us Cl. 260/2955 B 260/295 R 260/295 N,antibacterial agents, as are the corresponding 7- 760096 N hydroxymethy1compounds WhlCh are prepared by hy- 51 Int. Cl 607d 31/36 drolysis ofthe final Products where Q is [58' Field of Search H 260/2955 B, 295 N296 N alkanoyloxyrnethyl). A further process comprises reactingl,4-dihydro-7-methy1-4-oxo-1,8-naphthyr1dme- [56] References Citedg-oxide (V) with a hydroxymethylating agent to prouce UMTED STATESPATENTS -dihydro-3-hydroxymethyl-7-methy1-4-oxo-1,S-naph- 3,149.10-19/1964 Lesher et a1. 260/2955 B h idi g xide (V1) and oxidizing VI toproduce 3.225.055 12/1965 Lesher et a1. 260/2955 B OTHER PUBLICATIONSUrbanski, .1. Chem. Soc.. London, pp. 132134, (1947),QD1C.6. Klingsherg,Pyridine and Its Derivatives, part 3, Interscience Pub pp. 182-191,(1962), OD 401 K5 C2.

Primary lituminw-Alan L. Rotman Attorney. Agent, or Firm-Robert K. Bair;B. Woodrow Wyatt 3-carboxy-1,4-dihydro-7methy1-4-oxo-1,8-naphthyridine-S-oxide (VII). The 8-oxide (V11) isconverted in three steps via the 7-(1ower-a1kanoy1oxymethyl) compound tol-ethy1- 1,4-dihydro-7-hydroxymethy1-4-oxo-l,S-naphthyridine-3-carboxy1ic acid.

12 Claims, No Drawings PREPARATION OFl-ALKYL-l,4-DIHYDRO-7-SUBSTITUTED-4- OXO-l,8-NAPHTHYRIDINlE-3-CARBOXYLICACIDS VIA THE -3HYDROXYMETHY L NAL S PROCESS AND INTERMEDIATES Thisinvention relates to steps in the process of preparingl,8-naphthyridine-B-carboxylic acids and to compositions used therein.

The invention in a process aspect comprises the combination of the threesteps of reacting l,4-dihydro-4- oxo-7-Q-l,S-naphthyridine (I), which istautomeric with 4-hydroxy-7-Q-l ,8-naphthyridine (IA), with ahydroxymethylating agent to produce l,4-dihydro-3-hydroxymethyl-4-oxo-7-Q- l ,8-naphthyridine (II which is tautomeric with4-hydroxy-3hydroxymethyl- 7-Q-l.8-naphthyridine (llA), reacting II (orIIA) with a loweralkylating agent to produce l-(lower-alkyl)-l,4-dihydro-3-hydroxymethyl-4-oxo-7-Q-l,8- naphthyridine (III), andreacting III with an oxidizing agent capable of converting CH OH to-COOH to produce l-( lower-alkyl l ,4-dihydro-4-oxo-7-Q- l ,8-naphthyridine-3-carboxylic acid (IV), where Q is lower-alkyl,lower-alkanoyloxymethyl, 4(or 3)-pyridyl or 4(or 3)pyridyl having one ortwo lower-alkyl substituents. The final products (IV) are knownantibacterial agents, as are the corresponding 7-hydroxymethyl compoundswhich are prepared by hydrolysis of the final products where Q islower-alkanoyloxymethyl. In addition to said combination of the threesteps, other process aspects of the invention are each individual stepand the two consecutive combinations of two steps.

The invention in its composition aspect resides in the compounds:l,4-dihydro-3-hydroxymethyl-4-oxo-7-Q- l.8naphtliyridine and itstautomeric 4-hydroxy-3- hydroxymethylJQ-l,8-naphthyridine of therespective fatalities! L II IIA 7 andl(lower-alkyl)-],4-dihydro-3-hydrog/hW4 oxo-7-Q: l ,S-naphthyridine offormula III III where R, is lower-alkyl and Q in each of the formulasIl, 11A and Ill is defined as hereinabove.

Another process aspect of the invention comprises the two-stepcombination as well as the individual steps of reactingl,4-dihydro-7-methyl-4-oxol ,8-naphthyridine-S-oxide (V), which istautomeric with 4-hydroxy- '7-methyl-l,8-naphthyridine-8-oxide (V), witha hyproduce 3-carboxy-l ,4-dihydro-7-methyl-4-oxo-l ,8-naphthyridine-8-oxide (VII), which is tautomeric with 3-carboxy-4hydroxy-7-methyl-1,8-naphthyridine-8- oxide (VIIA). The 8-oxide (Vll orVllA) is then converted by known means to produce l-ethyl-l ,4-dihydro-7-hydroxymethyl-4-oxo-1,8-naphthyridine-3- carboxylic acid byfirst reacting it (or its lower-alkyl ester) with a lower-alkanoic acidanhydride to produce 7-(lower-alkanoyloxymethyl)-1,4-dihydro-4-oxo-l ,8-naphthyridine-3-carboxylic acid (or its lower-alkyl ester), ethylatingthe latter to produce 7-(loweralkanoyloxymethyl)- l -ethyl-l,4-dihydro-4-oxol ,8- naphthyridine-3-carboxylic acid (or itslower-alkyl ester) and heating the latter with aqueous alkali metalhydroxide solution to produce said corresponding 7- hydroxymethyl-l,8-naphthyridine-B-carboxylic acid.

The term lower-alkyl, as used herein, e.g., as represented by R, informula III or as a substituent of 4(or 3)-pyridyl when represented by Qin formulas II, "A or [11, means alkyl radicals having from 1 to 6carbon atoms which can be arranged as straight or branched chains,illustrated by methyl, ethyl, n-propyl, isopropyl,

n-butyl, sec-butyl, isobutyl, n-amyl, n-hexyl, and the like.

The term lower-alkanoyl, as used herein, e.g., in the definition of theQ substituent as loweralkanoyloxymethyl in formulas II, A or III, meansalkanoyl radicals having from one to six carbon atoms, including thestraightand branched-chain radicals, illu'strated by formyl, acetyl,propionyl (propanoyl). butyryl (butanoyl), isobutyryl(2-methylpropanoyl) and 'caproyl (hexanoyl).

Illustrative of the Q substituent in formulas III, IV, IVA, and V whereQ is 4(or 3)-pyridyl having one or two lower-alkyl substituents are thefollowing: 2-methyl-4-pyridyl, 2,6-dimethyl-4-pyridyl, 3-methyl-4-pyridyl, 2-methyl-3-pyridyl, 6-methyl-3-pyridyl (prefca oa oa oa a n nerably named 2-methyl-5-pyridyl), 2,3-dimethyl-4- pyridyl, 2,5-dimethyl4-pyridyl, 2-ethyl-4-pyridyl, 2-isopropyl-4-pyridyl,2-n-butyl-4-pyridyl, 2-n-hexyl-4- pyridyl, 2,6-diethyl-4-pyridyl,2,6-diethyl-3-pyridyl, 2,6-diisopropyl-4-pyridyl,2,6-di-n-hexyl-4-pyridyl, and the like. Because of ready availability,ease of preparation and/or high antibacterial activity of the finalproducts, i.e., the l-(lower-alkyl)-l,4-dihydro-7-[mono(or di)-(lower-alkyl)-4(or 3 )-pyridyl]4-oxo-l ,8 naphthyridine-3-carboxylicacids, preferred embodiments of this group are those where 4(or3)-pyridyl is substituted by one or two methyls, especially the2-methyl-4-pyridyl and 2,6-dimethyl-4-pyridyl compounds. Other preferredembodiments are those having unsubstituted-4(or 3)-pyridyl as Q.

As shown above, l,4-dihydro-3hydroxymethylJ-Q- 4-1 ,8-naphthyridine offormula II is tautomeric with 4-hydroxy-3-hydroxymethyl-7-Q-l,8-naphthyridine of formula IlA. As withall tautomeric systems, the rate of the transformation II 211A and theratio II/lIA are dependent on the thermodynamic environment, includingthe state of aggregation; so that measurements by any particulartechniques do not necessarily have validity except under the conditionsof the measurement, thereby, among other consequences, giving rise toproblems for any simple designation of the physical embodiments. Thus,measurements of the infrared spectra, in potassium bromide admixture, orin chloroform or mineral oil, indicate existence predominantly as ll andthe names of the compounds herein therefore are preferably based onstructure ll, although it is understood that either or both structuresare comprehended.

The intermediate 1,4-dihydro-4-oxo-7-Q-l,8- naphthyridines (l) ortautomers (lA) are either known or, where novel, are prepared from knowncompounds by methods illustrated hereinbelow. One such method, which isdisclosed and claimed in copending application Ser. No. 335,733, filedFeb. 26, 1973, comprises the steps of reacting cyclic alkylidenylN-(6-Q-2- pyridyl)aminomethylenemalonate, where Q is loweralkyl, 4(or 3)-pyridy|, or 4(or 3)-pyridyl having one or two lower-alkylsubstituents. with an oxidizing agent capable of converting pyridines topyridine-N-oxides to produce cyclic alkylidenyl N-(6-O-l-oxo-2-pyridyl-)aminomethylenemalonate, where Q is lower-alkyl, l-oxo-4-(or 3)-pyridylor l-oxo-4(or 3)-pyridyl having one or two lower-alkyl substituents,heating said 6-Q-l-oxo-2-pyridyl compound to produce 1,4- dihydro-4-oxo-7-Q'-l,8-naphthyridine-8-oxide and then converting said 8-oxide to thecorresponding 1,4- dihydro-4-oxo -7 Q-l,8-naphthyridine. Illustrationsof this method aregiven below in Examples 64-1 10.

The molecular structures of the composition aspects (ll, HA and III) ofour invention were assigned on the basis of evidence provided byinfrared, ultraviolet and nuclear magnetic resonance spectra, bychromatographic mobilities, and, by the correspondence of calculated andfound values for the elementary analyses for representative examples.

The manner of making and using the instant invention will now begenerally described so as to enable a person skilled in the art ofchemistry to make and use the same, as follows:

The reaction of l,4-dihydro-4-oxo7-Q-l ,8- naphthyridine (I) or itstautomeric 4-hydroxy-7-Q-l,8- naphthyridine (IA) with ahydroxymethylating agent to producel,4-dihydro-3hydroxymethyl-4-oxo-7-Q-l,8- naphthyridine (ll) or itstautomeric 4-hydroxy-3- hydroxymethyl-7-O-1,8-naphthyridine (HA) iscarried out preferably by reacting l (or 1A) with aqueous formaldehydeunder alkaline conditions.

The reaction of l,4-dihydro-3-hydroxymethyl-4-oxo- 7-1.8-naphthyridine(ll) or its tautomeric 4-hydroxy-3- hydroxymethyl-7-Q-l,S-naphthyridine(lIA) with a lower-alkylating agent to product l-(lower-alkyl)-l,4-dihydro-3-hydroxymethyl-4-oxo-7-Q- l ,8- naphthyridine (III) isgenerally carried out by reacting said compound of formula II or IlAwith a lower-alkyl ester of a strong inorganic acid or an organicsulfonic acid, said ester having the formula R,-An, where An is an anionof a strong inorganic acid or an organic sulfonic acid, e.g., chloride,bromide, iodide, sulfate, methanesulfonate, benzenesulfonate, andpara-toluenesulfonate, and R, is lower-alkyl. This alkylation ispreferably run using a slight excess of the alkylating agent althoughequimolar quantities give satisfactory results. The chloride, bromide oriodide is preferred be cause of the ready availability of the requisiteloweralkyl halides; and the reaction is carried out preferably in thepresence of an acid-acceptor. The acid-acceptor koxides, sodium amide,and the like. The purpose of 7 the acid-acceptor is to take up thehydrogen halide (or HAn) which is split out during the course of thereaction. The reaction is preferably carried out in the presence ofasuitable solvent which is inert under the reaction conditions, e.g., asolvent such as lower-alkanol, acetone, dioxane, dimethylformamide,dimethyl sulfoxide, hexamethyl phosphoramide, or a mixture of solvents,e.g., a mixture of water and a lower-alkanol. The reaction is generallycarried out at a temperature between about room temperature (about2025C.) and 150C, preferably heating on a steam bath in a stirredmixture of dimethylformamide and anhydrous potassium carbonate.

The reaction of l-(lower-alkyl)-l ,4-dihydro-3-hydroxymethyl-4-oxo-7-Q-l,S-naphthyridine (lll) with an oxidizing agentto produce l-(lower-alkyl)-l ,4- dihydro-4-oxo-7-Q- l,S-naphthyridine-3-carboxylic acid (IV) is generally carried out byreacting Ill with an oxidizing agent capable of converting hydroxymethylto carboxy. Such oxidizing agents are, for example, an alkalipermanganate, e.g., KMnO an alkali dichromate, e.g., Na Cr O nitricacid, and the like. The reaction conditions vary and are dependent uponthe particular oxidizing agent used. For example, oxidation withpotassium permanganate is conveniently 'run at low temperature,preferably below 20C., in a basic medium, preferably in pyridine whichalso acts as solvent or in aqueous sodium or potassium hydroxidesolution; two to three moles of potassium permanganate per mole ofthe3-hydroxymethyl compound are preferably used. Oxidation using dichromateis conveniently run in an aqueous acidic medium preferably using, forexample, per mole of sodium dichromate three moles of the3-hydroxymethyl compound in about four moles of sulfuric acid; thereaction temperature is kept preferably no higher than about 20C. duringaddition of the dichromate salt in water to the hydroxymethyl compoundin sulfuric acid (sp. gr. 1.84) and then allowing it to rise to about3550C. to accelerate the reaction. Oxidation with concentrated nitricacid (sp. gr. 1.42) is conveniently run by slowly adding in smallportions the 4-hydroxymethyl compound to a four to six molar excess ofthe nitric acid kept between about 20-30C. during the addition, and thenpreferably allowing the reaction mixture to stand at room temperature(about 20-25C.) overnight, i.e., about 15-16 hours, and then heating itfor about 1 hour on a steam bath.

The best mode contemplated for carrying out the invention is now setforth as follows:

EXAMPLE 1 l,4-Dihydro-3-hydroxymethyl-7-methyl-4-oxo-l ,8- naphthyridineTo a solution containing 1.6 g. of l,4-dihydro-7-methyl-4-oxo-l,8-naphthyridine (tautomeric with 4-hydroxy-7-methyl-l,8-naphthyridine), 5.5 ml. of 2N aqueous potassiumhydroxide solution and 10 ml. of water was added with stirring 0.8 ml.of formaldehyde (35-40%) and the resulting reaction mixture was heatedon a steam bath for 2 /2 hours. After standing at room temperature(about 20-25C.) overnight (about 18 hours), the reaction mixture wasfiltered and the filtrate was cooled in an ice bath. The resultingprecipitate was collected, washed with water, dried and found to have amelting point greater than 300C. The solid product was recrystallizedfrom ml. of dimethyl formamide using decolorizing charcoal, washed withether, dried in vacuo at 70C. to yield 0.6 g. 1,4-dihydro-3-hydroxymethyl-7-methyl-4-oxo-1,8- naphthyridine, which istautomeric with 4-hydroxy-3- hydroxymethyl-7-methyl-l ,8-naphthyridine.

EXAMPLE 2 l-Ethyl-l ,4-dihydro-3-hydroxymethyl-7-methyl-4-oxo-1,8-naphthyridine To a stirred suspension heated on a steam bath andcontaining 3.8 g. of l,4-dihydro-3-hydroxymethyl-7-methyl-4-oxo-l,8naphthyridine in 30 ml. of dimethylformamide is added8.3 g. of anhydrous potassium carbonate and the mixture is stirred forabout fifteen minutes. To the stirred hot mixture is added 3.8 g. ofethyl iodide and the resulting mixture is stirred with heating on thesteam bath for ninety minutes. The hot reaction mixture is filtered andthe filtrate chilled. The resulting crystalline precipitate iscollected, triturated with warm water..washed sparingly with warm waterand dried in vacuo at 60C. to yield l-ethyl-l,4-dihydro-3-hydroxymethyl-7-methyl-4-oxo-l,8-naphthyridine. if desired. thiscompound can be re-crystallized from dimethylformamide.

EXAMPLE 3' l-Ethyl-l .4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-B-carboxylic acid A suspension of 2.2 g. ofl-ethyl-l,4-dihydro-3- hydroxymethyl-7-methyl-4-oxo-l,8naphthyridine in25 ml. of pyridine and 5 ml. of water is stirred and cooled to 10C. inan ice bath. Solid potassium permanganate (5 g.) is added in smallportions over the course ofabout 55 minutes. The temperature is notallowed to rise above C. and small amounts of water totalling ml. isadded during the course of the addition. The resulting mixture isstirred about minutes longer at l0-20C. and then filtered throughinfusorial earth. The cake of collected manganese dioxide is washed witha little water and the combined filtrates are treated with saturatedaqueous sodium bisulfite solution until the excess permanganate isdestroyed. The pale yellow solution is then acidified with excess 6Nhydrochloric acid. After cooling in ice, the precipitated solid iscollected by vacuum, rinsed with fresh water and sucked as dry aspossible. The material is recrystallized from 12 ml. ofdimethylformamide and dried for 18 hours in a vacuum oven (80C.). Thereis obtained, as pale yellow crystals,l-ethyl-l,4-dihydro-7-methyl-4-oxo-l,8- naphthyridine-3-carboxylic acid,m.p. 232234C. A mixed melting point with authentic material isundepressed.

The above oxidation also is carried out by slowly adding with stirring asolution of 3.2 g. of sodium dichromate in 2.0 ml. of water to 7.06 g.of l-ethyl-l,4 dihydro-3-hydroxymethyl-7-methyl-4-oxo-l,8- naphthyridinein 2.4 ml. of sulfuric acid (sp. gr. 1.84) and 2.4 ml. of water, keepingthe reaction temperature below 20C. Stirring of the reaction mixture iscontinued while allowing the reaction temperature to rise to C. Thereaction mixture is diluted with an equal volume of water; the resultingmixture is chilled in an ice bath; and. the resulting precipitate iscollected. washed with water, dried and recrystallized fromdimethylformamide to yield l-ethyl-l,4-dihydro-7-methyl-4- oxo-l,8-naphthyridine-3-carboxylic acid.

This oxidation also is run as follows: To 6.20 ml. of concentratednitric acid (sp. gr. 1.42) kept between 2030C. is slowly added inportions with stirring 4.4 g. ofl-ethyl-l,4-dihydro-3-hydroxymethyl-7-methyl-4- oxo-l,8-naphthyridine.The reaction mixture is then allowed to stand at room temperature(20-25C.) for about 16 hours and is next heated on a steam bath for -1hour. The hot reaction mixture is diluted with an equal volume of hotwater and the resulting mixture is chilled in an ice bath. The resultingprecipitate is collected, washed with water, dried and recrystallizdfrom dimethylformamide to yield l-ethyl-l,4-dihydro-7- methyl-4oxo-l,S-naphthyridine-3-carboxylic acid.

Following the procedure described in Example 1 but using in place ofl,4-dihydro-7-methyl-4-oxo-l ,8- naphthyridine a molar equivalentquantity of the appropriate 1,4-dihydro-4-oxo-7-Q-l ,8-naphthyridine.the compounds of Examples 4-19 are obtained:

EXAMPLE 4 7-Ethyll ,4-dihydro-3-hydroxymethyl-4-oxo-l ,8- naphthyridineusing 7-ethyl-l,4-dihydro-4-oxo-l,8- naphthyridine.

EXAMPLE 5 l,4Dihydro-3-hydroxymethyl-4-oxo-7-n-propyl-l ,8-naphthyridine using l,4-dihydro-4-oxo-7-n-propyl-l ,8- naphthyridine.

EXAMPLE 6 1,4-Dihydro-3-hydroxymethyl-7-isobutyl-4-oxo-l ,8-naphthyridine using l,4-dihydro-7-isobutyl-4-oxo-l,8- naphthyridine.

EXAMPLE 7' 7-n-l-lexyl-l ,4-dihydro-3-hydroxymethyl-4-oxol ,8-naphthyridine using 7-n-hexyl-l,4-dihydro-4-oxo-l,8- naphthyridine.

EXAMPLE 8.

7Acetoxymethyl-l ,4-dihydro-3-hydroxymethyl-4- oxol,8-naphthyridineusing 'J-acetoxymethyl-IA- dihydro-4-oxo-l ,8-naphthyridine.

EXAMPLE 9 l,4-Dihydro-3-hydroxymethyl-4-oxo-7- propionoxymethyH,8-naphthyridine using 1,4- dihydro-4-oxo-7-propionoxymethyl-l,8-naphthyridine.

EXAMPLE l0 l,4-Dihydro-3-hydroxymethyl-7-isobutyroxymethyl- 4-oxol,S-naphthyridine using l,4-dihydro-7- isobutyroxymethyl-4-oxo l,8-naphthyridine.

EXAMPLE ll 7Hexanoyloxymethyl-l ,4-dihydro-3-hydroxymethyl-4-oxo-l,8-naphthyridine using 7-hexanoyloxymethyll,4-dihydro-4-oxol,8-naphthyridine.

EXAMPLE 51 l-Ethyl-7-hexanoyloxymethyl-l,4-dihydro-4-oxol,8-naphthyridine-3-carboxylic acid using l-ethyl-7-hexanoyloxymethyll ,4-dihydro-3-hydroxymethyl-4- oxol ,S-naphthyridine.

EXAMPLE 52 l-Ethyl-l,4-dihydro-4-oxo-7-(4-pyridyl)-1,8-naphthyridine-3-carboxylic acid using l-ethyl-l,4-dihydro-3-hydroxymethyl-4-oxo-7-(4-pyridyl)-l,8- naphthyridine.

EXAMPLE 53 l ,4Dihydro-l-methyl-4-oxo-7-(4-pyridyl)-1,8-

' naphthyridine-3-carboxylic acid using 1,4-dihydro-3-hydroxymethyl-l-methyl-4-oxo-7-(4-pyridyl)-1,8- naphthyridine.

EXAMPLE 54 l,4-Dihydro-4-oxo-l-n-propyl-7-(4-pyridyl)-1,8-naphthyridine-3-carboxylic acid using 1,4-dihydro-3-hydoxymethyl-4-oxo-l-n-propyl-7-(4-pyridyl)-l,8- naphthyridine.

EXAMPLE 55 l .4-Dihydro-l-isobutyl-4-oxo-7-(4-pyridyl)-1,8-naphthyridine-3-carboxylic acid using l,4-dihydro-3-hydroxymethyhl-isobutyl-4-oxo-7-(4-pyridyl)-l,8- naphthyridine.

EXAMPLE 56 l-n-Hexyl-l.4-dihydro-4-oxo-7-(4-pyridyl)1,8-naphthyridine-3-carboxylic acid using l-n-hexyl-l,4-dihydro-3-hydroxymethyl-4-oxo-7-(4-pyridyl)-l,8- naphthyridine.

EXAMPLE 57 l-Ethyl-l,4-dihydro-4-oxo-7-(3-pyridyl)-l,8-naphthyridine-3-carboxylic acid using l-ethyl-1,4-dihydro-3-hydroxymethyl-4-oxo-7-(3pyridyl)-l,8- naphthyridine.

EXAMPLE 58 l-Ethyl-l ,4-dihydro-7-(2methyl-4-pyridyl)-4-oxol,8-naphthyridine-3-carboxylic acid usingl-ethyl-l,4- dihydro-3-hydroxymethyl-7-(2-methyl-4-pyridyl)-4- oxol,8-naphthyridine.

EXAMPLE 59 l-Ethyl-l .4-dihydro-7-( 3-methyl-4-pyridyl l ,8-naphthyridine-3-carboxylic acid using l-ethyl-l,4-dihydro-3-hydroxymethyl-7-( 3-methyl-4-pyridyl)-l ,8- naphthyridine.

EXAMPLE 60 l-Ethyl-7-(2-ethyl-4 -pyridyl)-l,4-dihydro4-oxo-l,8-naphthyridine-3-carboxylic acid using l-ethyl-7-(2- ethyl-4-pyridyl)- l.4-dihydro-3-hydroxymethyl-4-oxol,8-naphthyridine.

EXAMPLE 61 l-Ethyl-7-(3-ethyl-4-pyridyl)-l,4-dihydro-4-oxo-l,8-napthyridine-3-carboxylic acid using l-ethyl-7-(3- ethyl-4-pyridyl l,4-dihydro-3-hydroxymethyl-4-oxo- 1,8-naphthyridine.

EXAMPLE 62 l-Ethyll ,4-dihydro-7-(2,6-dimethyl-4-pyridyl )-4-oxo-l,8-naphthyridine-3-carboxylic acid using l-ethyl-1,4-dihydro-3-hydroxymethyl-7-(2,6-dimethyl-4-pyridyl)-4-oxo-1,8-naphthyridine.

EXAMPLE 63 l-Ethyl-l ,4-dihydro-7-( 3,5-dimethyl-4-pyridyl )-4-oxo-l,S-naphthyridine-3-carboxylic acid using l-ethyll,4-dihydro3-hydroxymethyl-7-(3.5-dimethyl-4- pyridyl )-4-oxol ,8-naphthyridine.

The following Examples 64-1 l0 illustrate the preparation of theintermediate 1,4-dihydro-4-oxo-7-Q-l,8- naphthyridines, said preparationbeing disclosed and claimed in copending U.S. Pat. application Ser. No.335,733.

EXAMPLE 64 Cyclic isopropylidenyl N-(6-methyl-l-oxo-2-pyridyl)aminomethylenemalonate To a solution containing 26.2 g. of cyclicisopropylidenyl N-(6-methyl-2-pyridyl)aminomethlenemalonate in 150 ml.of chloroform is slowly added with stirring 19 g. of3-chloroperbenzoicacid, keeping the reaction temperature below about 40C. After theaddition is completed, the reaction mixture is heated on a steam bathfor about 30 minutes. The reaction mixture is extracted successivelywith 50 ml. of ice cold 10% aqueous sodium bicarbonate solution, ml. ofwater, 30 ml. of ice cold 10% aqueous sodium bicarbonate solution and 25ml. of water. The resulting chloroform solution is washed with water,dried over anhydrous potassium carbonate, filtered and the filtrateconcentrated in vacuo to remove the chloroform. The remaining solid istriturated with isopropyl alcohol and then recrystallized from ethanolusing decolorizing charcoal to yield cyclic isopropylidenylN-(6-methyl-l-oxo-2-pyridyl- )aminomethylenemalonate, m.p. 222223C. withdecomposition.

The above preparation also is carried out using a molar equivalentquantity of other oxidizing agents in a suitable solvent inert under thereaction conditions, e.g., use of peracetic acid in acetic acid.

EXAMPLE 65 l,4Dihydro-7-methyl-4-oxo-l ,8-naphthyridine-8- oxide To aml. portion of diethyl phthalate heated to 275C. is added with stirring2.78 g. ofcyclic isopropylidenylN-(6-methyll-oxo-2-pyridyl)aminomethylenemalonate. The stirred reactionmixture is heated at the same temperature for two minutes and thenallowed to cool to room temperature. The precipitated solid iscollected, washed well with ether and airdried to yield the product,l,4-dihydro-7-methyl-4-oxol,8-naphthyridine-8-oxide, which is tautomericwith 4-hydroxy-7-methyl-l,S-naphthyridine8-oxide. Recrystallization, ifdesired, is carried out using dimethylformamide.

The above cyclization also is carried out in 225 ml. of refluxingDowtherm A in place of the diethyl phthalate.

EXAMPLE 66 l,4-Dihydro-7-methyl-4-oxo-l ,8-naphthyridine A mixturecontaining 8.75 g. of 1,4-dihydro-7-methyl-4-oxo-l,8-naphthyridine-8-oxide, 250 ml. of absolute ethanol and5 g. of Raney nickel is hydrogenated at about 25C. in a Parr apparatususing an initial pressure of 55 p.s.i. of hydrogen. The catalyst isfiltered off, the filtrate treated with decolorizing charcoal andfiltered, and the filtrate concentrated in vacuo and chilled. Theprecipitate is collected, recrystallized from ethanol and dried over Pat C. overnight to yield l,4-dihydro-7-methyl-4-oxo-l,S-naphthyridine,m.p. 240-24lC.

Following the procedure described in Example 64 but using in place ofcyclic isopropylidenyl N-(6- methyl-2-pyridyl)aminomethylenemalonate amolar equivalent quantity of the appropriate cyclic alkylidenylN-(6-Q-2-pyridyl)aminomethylenemalonate, the compounds of Examples 67-81are obtained:

EXAMPLE 67 Cyclic isopropylidenyl N-(6-ethyl-l-oxo-2-pyridyl-)aminomethylenemalonate using cyclic isopropylidenylN-(6-ethyl-2-pyridyl)aminomethylenemalonate, the latter prepared byreacting 2-amino-6-ethylpyridine with a mixture of triethyl orthoformateand cyclic isopropylidenyl malonate.

EXAMPLE 68 Cyclic isopropylidenyl N-(l-oxo-6-n-propyl-2-pyridyl)aminomethylenemalonate using cyclic isopropylidenylN-(6-n-propyl-2-pyridyl)aminomethylenemalonate, the latter prepared byreacting Z-amino-6-n-propylpyridine with a mixture of triethylorthoformate and cyclic isopropylidenyl malonate.

EXAMPLE 69 Cyclic isopropylidenyl N-(6-isopropyl-l-oxo2-pyridyl)aminomethylenemalonate using cyclic isopropylidenyll\l(6-isopropyl-2-pyridyl)aminornethylenemalonate, the latter preparedby reacting Z-amino-6-isopropylpyridine with a mixture of triethylorthoformate and cyclic isopropylidenyl malonate.

EXAMPLE 7O EXAMPLE 71 Cyclic isopropylidenylN-(6-n-hexyl-l-oxo-2-pyridyl- )aminomethylenemalonate using cyclicisopropylidenyl N-(6-n-hexyl-2-pyridyl)aminomethylenemalonate, thelatter prepared by reacting 2-amino-6-n-hexylpyridine with a mixture oftriethyl orthoformate and cyclic isopropylidenyl malonate.

EXAMPLE 72 Cyclic 3-pentylidenyl N(6-methyl-l-oxo-2-pyridyl-)aminomethylenemalonate using cyclic 3-pentylidenylN-(6-methyl-2-pyridyl)aminomethylenemalonate, the latter prepared byreacting 2-amino-6-methylpyridine with a mixture of triethylorthoformate and cyclic 3- pentylidenyl malonate.

EXAMPLE 73 Cyclic Z-butylidenyl N-(6-methyl-l-oxo-2-pyridyl-)aminomethylenemalonate using cyclic Z-butylidenylN-(6-methyl-2-pyridyl)aminomethylenemalonate, the latter prepared byreacting 2-amino-6-methylpyridine with a mixture of triethylorthoformate and cyclic 2- butylidenyl malonate.

EXAMPLE 7-4 Cyclic 4-heptylidenyl N-(-methyl-l-oxo-2-pyridyl-)aminomethylenemalonate using cyclic 4-heptylidenylN-(6-methyl-2-pyridyl)aminomethylenemalonate, the latter prepared byreacting 2-amino-6-methylpyridine with a mixture of triethylorthofiormate the cyclic 4- heptylidenyl malonate.

EXAMPLE 75 Cyclic isopropylidenyl N-[ l-oxo-6-( l-oxo-4-pyridyl)-2-pyridyl]aminomethylenemalonate using cyclic isopropylidenylN-[6-(4-pyridyl)-2-pyridyl- ]aminomethylenemalonate. the latter preparedby reacting 2-amino-6-(4-pyridyl)pyridine with a mixture of triethylorthoformate and cyclic isopropylidenyl malonate.

EXAMPLE 76 Cyclic isopropylidenyl N-[ l-0xo-6-( l-oxo-3-pyridyl)-2-pyridyl]aminomethylenemalonate using cyclic isopropylidenylN-[6-(3-pyridyl)-2-pyridyl- ]aminomethylenemalonate, the latter preparedby reacting 2-amino-6-(3-pyridyl)pyridine with a mixture of triethylorthoformate and cyclic isopropylidenyl malonate.

EXAMPLE 77 Cyclic isopropylidenyl N-ll-oxo-6-(2-methyl-l-oxo-4-pyridyl)-2-pyridyl]aminomethylenemalonate using cyclic isopropylidenylN-{6-(2-n1ethyl-4-pyridyl)-2- pyridyl]aminomethylenemalonate, the latterprepared by reacting 2-amino-6-(2-methyl-4-pyridyl)pyridine with amixture of triethyl orthoformate and cyclic isopropylidenyl malonate.

EXAMPLE 78 Cyclic isopropylidenyl N-[l-oxo-6-(2-ethyl-l-0xo-4-pyridyl)-2-pyridyllaminomethylenemalonate using cyclic isopropylidenylN-[6-(2-ethyl-4-pyridyl)-2-pyridyl- Jaminomethylenemalonate, the latterprepared by reacting 2-amin0-6-(2-ethyl-4-pyridyl)pyridine with amixture of triethyl orthoformate and cyclic isopropylidenyl malonate.

EXAMPLE 79 Cyclic isopropylidenyl N-[ l-oXo-6-(3-ethyl-l-oxo-4-pyridyl)-2-pyridyl]aminomethylenemalonate using cyclic isopropylidenylN-[6-(3-ethyl-4-pyridyl)-2-pyridyl- ]aminomethylenemalonate, the latterprepared by reacting 2-amino-6-(3-ethyl-4-pyridyl)pyridine with amixture of triethyl orthoformate and cyclic isopropylidenyl malonate.

EXAMPLE 8O Cyclic isopropylidenyl N-[l-oxo-6(2,6-dimethyl-loxo-4-pyridyl )-2-pyridyl 1aminomethylenemalonate usingcyclic isopropylidenyl N-[6-(2,6-dimethyl-4-pyridyl)-2-pyridyl]aminomethylenemalonate, the latter prepared byreacting 2-amino-6-(2,6-dimethyl-4- pyridyl)pyridine with a mixture oftriethyl orthofon mate and cyclic isopropylidenyl malonate.

EXAMPLE 8] Cyclic isopropylidenylN-[l-oxo-6-(3,5-dimethyl-loxo-4-pyridyl)-2-pyridyl]aminomethylenemalonateusing cyclic isopropylidenyl N-[6-(3,5-dimethyl-4-pyridyl)-2-pyridyl]aminomethylenemalonate, the latter prepared byreacting 2-amino-6-(3,5-dimethyl-4- pyridyl)pyridine with a mixture oftriethyl orthoformate and cyclic isopropylidenyl malonate.

Following the procedure described in Example 65 but using in place ofcyclic isopropylidenyl N-(6-methyl-l-oxo-2-pyridyl)aminomethylenemalonate a molar equivalentquantity of the appropriate cyclic alkylidenylN-(6-Q-l-oxo-2-pyridyl)aminomethylenemalonate, the compounds of Examples82-97 are obtained:

EXAMPLE 82 7-Ethyl-l,4-dihydro-4-oxo-l,8-naphthyridine-8- oxide usingcyclic isopropylidenylN-(6-ethyl-l'oxo-2-pyridyl)aminomethylenemalonate.

EXAMPLE 83 l.4Dihydro-4-oxo-7-n-propyll ,8-naphthyridine-8- oxide usingcyclic isopropylidenylN-(l-oxo-6-npropyl-Z-pyridyl)aminomethylenemalonate.

EXAMPLE 84 l.4-Dihydro-7-isopropyl-4-oxol ,8-naphthyridine-8- oxideusing cyclic isopropylidenylN-(o-isopropyl-loxo-Z-pyridyl)uminomethylenemulonate.

EXAMPLE 88 l ,4-Dihydro-7-methyl-4-oxo-1,8-naphthyridine-8- oxide usingcyclic 2-butylidenyl N-(6-methyl-l-oxo-2-pyridyl)uminomethylenemalonate.

EXAMPLE 89 l.4-Dihydro-7-methyl-4-oxol ,8-naphthyridine-8- oxide usingcyclic 4-heptylidenyl N-(6-methyl-l-oxo-2-pyridyl)zuninomethylenemalonate.

EXAMPLE 9O l,4-Dihydro-4-oxo-7-( l-oxo-4-pyridyl)- l,S-naphthyridine-8-oxide using cyclic isopropylidenyl N-[loxo-6-(l-oxo-4-pyridyl)-2-pyridyl]aminomethylenemalonate.

EXAMPLE 9] 1 ,4-Dihydro-4-oxo-7-( l-oxo-3-pyridyl )-1,8-naphthyridine-8-oxide using cyclic isopropylidenylN-[1-oxo-6-(1-oxo-3-pyridyl)-2-pyridylJaminomethylenemalonate.

EXAMPLE 92 l,4-Dihydro-4-oxo-7-( Z-methyll -oxo-4-pyridyll,8-naphthyridine-8-oxide using cyclic isopropylidenyl N-[l-oxo-6-(2-methyll -oxo-4-pyridyl)-2-pyridyl- ]aminomethylenemalonate.

EXAMPLE 93 l ,4-Dihydro-4-oxo-7-(3-methyl-1-oxo-4-pyridyl)-l,8-naphthyridine-8-oxide using cyclic isopropylidenyl N-[l-oxo-6-(3-methyl-1-oxo-4-pyridyl)-2-pyridyl- ]aminomethylenemalonate.

EXAMPLE 94 l,4-Dihydro-4-oxo-7-( 2-ethyll -oxo-4-pyridyl )-l ,8-naphthyridine-8-oxide using cyclic isopropylidenyl N-[l-oxo-6-(2-ethyl-l-oxo-4-pyridyl)-2-pyridyl- ]aminomethylenemalonate.

EXAMPLE 95 l,4-Dihydro-4-oxo-7-( 3-ethyll -oxo-4-pyridyl l .8-naphthyridine-8-oxide using cyclic isopropylidenyl N-l-oxo-6-(3-ethyl-l-oxo-4-pyridyl)-2-pyridyl- ]aminomethylenemalonate.

EXAMPLE 96 l,4-Dihydro-4-oxo-7-( 2,6-dimethyll -oxo-4-pyridyl)-1,8-naphthyridine-8-oxide using cyclic isopropylidenylN-[l-oxo-6-(2,6-dimethyl-l-oxo-4-pyridyl)-Z-pyridyl]aminomethylenemalonate.

EXAMPLE 97 l,4-Dihydro-4-oxo-7-(3,5-dimethyl-l-oxo-4- pyridyl)-l,8-naphthyridine-8-oxide using cyclic isopropylidenylN-{l-oxo-6-(3,5-dimethyl-l-oxo-4-pyriclyl)-2-pyridyl]aminomethylenemalonate.

Following the procedure described in Example 66, but using in place ofI,4-dihydro-7-methyl-4-oxo-l,8- naphthyridine-8-oxide a molar equivalentquantity of the appropriate1,4-dihydro-7-Q-4-oxo-l,S-naphthyridine-S-oxide, the compounds ofExamples 98-1 10 are produced:

EXAMPLE 98 7-Ethyl-l,4-dihydro-4-oxo-l,8-naphthyridine using 7-ethyl-l,4-dihydro-4-oxo-l ,8-naphthyridine-8-oxide.

EXAMPLE 99 l,4-Dihydro-4-oxo-7-n-propyl-l ,8-naphthyridine usingl,4-dihydro-4-oxo-7-n-propyl-l ,S-naphthyridine- 8-oxide.

EXAMPLE lOO l,4-Dihydro-7-is0propyl-4-oxol ,8-naphthyridine usingl,4-dihydro-7-isopropyl-4-oxo-l ,8-naphthyridine-8-oxide.

EXAMPLE lOl 7-n-Butyl-l ,4-dihydro-4-0xol ,8-naphthyridine using7-n-butyl-1,4-dihydro-4-oxo-l ,8-naphthyridine-8- oxide.

EXAMPLE 102 7-n-Hexyl-1,4-dihydro-4-oxo-1,8-naphthyridine using7-n-hexyl-1,4-dihydro4-oxo-1 ,8-naphthyridine- 8-oxide.

EXAMPLE 103 1,4-Dihydro-4-oxo-7-(4-pyridyl)-1,S-naphthyridine usingl,4-dihydro-4-oxo-7-( l-oxo-4-pyridyl)l,8-naphthyridine-8-oxide.

EXAMPLE 104 l,4-Dihydro-4-oxo-7-( 3 -pyridyl)-1,S-naphthyridine usingl,4-dihydro-4-oxo-7-( l-oxo-3-pyridyl)-l,8-naphthyridine-8-oxide.

EXAMPLE 105 l ,4-Dihydro4-oxo-7-(2-methyl-4-pyridyl)-1,8- naphthyridineusing 1,4-dihydro-4-oxo7-(2-methyl-1- oxo-4-pyridyl)-l,S-naphthyridine-8-oxide.

EXAMPLE 106 l,4-Dihydro-4-oxo-7-(3-methyl-4-pyridyl)-l ,8- naphthyridineusing 1,4-dihydro-4-oxo-7-(3-methyl-1- oxo-4-pyridyl)-l,8-naphthyridine-S-oxide.

EXAMPLE I07 l,4-Dihydro-4-oxo-7-(2-ethyl-4-pyridyl)-1,8- naphthyridineusing l,4-dihydro-4-oxo-7-( Z-ethyll oxo-4-pyridyl l,8-naphthyridine-8-oxide.

EXAMPLE l08 l,4-Dih vdro-4-oxo-7-( 3-ethyl-4-pyridyl)- l ,8-naphthyridine using l.4-dihydro-4-oxo-7-( 3-ethyl l oxo-4-pyriclyl )-l8-naphthyridine-S-oxide.

EXAMPLE 109 l.4-Dihydro'4oxo-7-( 2 .6-dimethyl-4-pyridyl)- l ,8-miphthyridine using l,4-dihydro-4-oxo7'(2,6- dim ethyll -oxo-4-pyridyl l,8-11aphthyridine-8-oxide.

EXAMPLE 110 18 alkyl, lower-alkanoyloxymethyl, 4(or 3)-pyridyl or 4(or3)-pyridyl having one or two lower-alkyl substituents.

2. The process consisting of reacting 1,4-dihydro-4-oXo-7Q-1,8-naphthyridine with aqueous formaldehyde under alkalineconditions to produce 1,4-dihydro-3-hydroxymethyl-4-oxo-7-Q-l,8-naphthyridine, where Q is lower-alkyl, loweralkanoyloxymethyl, 4(or 3)- pyridyl or 4(or 3)-pyridyl having one or twoloweralkyl substituents.

3. The process consisting of reacting 1,4-dihydro-4- oxo-7'Q- l,S-naphthyridine with aqueous formaldehyde under alkaline conditions toproduce 1,4-dihydro-3- hydroxymethyl-4-oxo-7-Q-l,S-naphthyridine andreacting l,4-dihydro-3-hydroxymethyl-4-oxo-7-Q-l ,8- naph'thyridine witha lower-alkylating agent to produce l-(lower-alkyl)-l,4-dihydro-3-hydroxymethyl-4-oxo-7- Q-l,8-naphthyridine, where Q islower-alkyl, loweralkanoyloxymethyl, 4(or 3)-pyridyl or 4(or 3)-pyridylhaving one or two lower-alkyl substituents.

4. A compound selected lfrom l,4-dihydro-3-hydroxymethyl-4-oxo-7-Q-1,8-naphthyridine and its tautomeric4-hydroxy-3-hydroxymethyl-7-Q-l ,8- naphthyridine, where Q islower-alkyl, loweralkanoyloxymethyl, 4(or 3)-pyridyl or 4(or 3)-pyridylhaving one or two lower-alkyl substituents.

5. The compound according to claim 4 where Q is methyl.

6. l-(Lower-alkyl)-l,4-dihydro-3-hydroxymethyl-4-oxo-7-Q-l,8-naphthyridine, where Q is lower-alkyl,lower-alkanoyloxymethyl, 4(or 3)-pyridyl or 4(or 3)- pyridyl having oneor two lower-alkyl substituents.

7. The compound according to claim 6 where Q is methyl.

8. The process according to claim 1 where Q is methyl and thelower-alkylating agent is an ethylating agent to producel-ethyl-l,4-dihydro-7-methyl-4-oxol,8-naphthyridine-3-carboxylic acid.

9. The process according to claim 2 where O is methyl.

10. The process according to claim 3 where Q is methyl and thelower-alkylating agent is an ethylating agent.

11. The process consisting of reacting 1,4-dihydr0-7-methyl-4-oxo-1,S-naphthyridine-S-oxide with aqueous formaldehyde underalkaline conditions to produce 1,-4-dihydro-3-hydroxymethyl-7-methyl-4-oxo-1,8-naphthyridine-S-oxide andreacting the latter with an oxidizing agent capable of converting CH- OHto COOH to produce 3-carboxy-1,4-dihydro-7-methyl-4-oxo-l,8-naphthyridine-S-oxide.

12. The process consisting of reacting 1,4-dihydro-7-methyl-4-oxo-l,S-naphthyridine-Sl-oxide with aqueous formaldehyde underalkaline conditions to produce 1,-4-dihydro-3-hydroxymethyl-7-methyl-4-oxo-1,8-naphthyridine-8-oxide.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. Datedlnventofls) f. Lesher and Iionte G'r'ue'tt It is certified that errorappears in the above-identified patent and that said Letters Patent arehereby corrected as shown below:

Abstract, line 6, change "al-- to read alkyl)- and, line 7, omit 5 thebi ihg g add and line 1, omit Column 1, title, line 4, EHYDROXYIIE'I'HYL" should read B-HYDROXYNETHYL Column 1, line 6, omit "PROCESSAND INTERMEDIATES Column 1, line 36, "7Q" should read 7-Q Column 2, line64, between 4-" and "l, 8" insert oxo- Column 3, line 50, "7-1,8" shouldread 7-Q-l,8

Column 5, line 52, "product" should read produce H Column 1?, Claim 1,line #9, immediately following produce delete the comma.

d Column 1?, Claim 1, line 56, cude should read uce 3' e" n 77a led this1st dav of? Julv U75. ,l hec. ct of J J (SEAL) Attest:

C. I'LJISIEALL DRIP-3N RUTH C. MASON Commissioner of Patents AttestingOfficer and Trademarks FORM PO- 0 (10-69) USCOMM-DC eoavs-F-ss u.s.sovzmmzm PRINTING omcz: 930

Column 3, line 25, l-(or 3) should read 4(or 5)

1. THE PROCESS CONSISTING OF REACTING1,4-DIHYDRO-4-OXO-7Q-1,8-NAPHTHYRIDINE WITH AQUEOUS FORMALDEHYDE UNDERALKALINE CONDITIONS TO PRODUCE,1,4-DIHYDRO-3-HYDROXYMETHYL-4OXO-7-Q-1,8-NAPHTHYRIDINE, REACTING THELATTER WITH A LOWERALKYLATING AGENT TO PRODUCE1-(LOWER-ALKYL)-1,4-DIHYDRO-3HYDROXYMETHYL-4-OXO-7-Q-1,8-NAPHTHYRIDINE,AND REACTING SAID 1-(LOWER-ALKYL)-3-HYDROXYMETHYL COMPOUND WITH ANOXIDIZING AGENT CAPABLE OF CONVERTING -CH2OH TO -COOH TO PRODUCE1-(LOWER-ALKYL)-1,4-ODIHYDRO-4-OXO-7-Q-1,8NAPHTHYRIDINE-3-CARBOXYLICACID, WHERE Q IS LOWER-ALKYL, LOWER-ALKANOYLOXYMETHYL, 4(OR 3)-PYRIDYLOR 4(OR 3)-PYRIDYL HAVING ONE OR TWO LOWER-ALKYL SUBSTITUENTS.
 2. Theprocess consisting of reacting 1,4-dihydro-4-oxo-7-Q-1,8-naphthyridinewith aqueous formaldehyde under alkaline conditions to produce1,4-dihydro-3-hydroxymethyl-4-oxo-7-Q-1,8-naphthyridine, where Q islower-alkyl, lower alkanoyloxymethyl, 4(or 3)-pyridyl or 4(or 3)-pyridylhaving one or two lower-alkyl substituents.
 3. The process consisting ofreacting 1,4-dihydro-4-oxo-7-Q-1,8-naphthyridine with aqueousformaldehyde under alkaline conditions to produce1,4-dihydro-3-hydroxymethyl-4-oxo-7-Q-1,8-naphthyridine and reacting1,4-dihydro-3-hydroxymethyl-4-oxo-7-Q-1,8-naphthyridine with alower-alkylating agent to produce1-(lower-alkyl)-1,4-dihydro-3-hydroxymethyl-4-oxo-7-Q-1,8-naphthyridine,where Q is lower-alkyl, lower-alkanoyloxymethyl, 4(or 3)-pyridyl or 4(or3)-pyridyl having one or two lower-alkyl substituents.
 4. A compoundselected from 1,4-dihydro-3-hydroxymethyl-4-oxo-7-Q-1,8-naphthyridineand its tautomeric 4-hydroxy-3-hydroxymethyl-7-Q-1,8-naphthyridine,where Q is lower-alkyl, lower-alkanoyloxymethyl, 4(or 3)-pyridyl or 4(or3)-pyridyl having one or two lower-alkyl substituents.
 5. The compoundaccording to claim 4 where Q is methyl. 6.1-(Lower-alkyl)-1,4-dihydro-3-hydroxymethyl-4-oxo-7-Q-1,8-naphthyridine,where Q is lower-alkyl, lower-alkanoyloxymethyl, 4(or 3)-pyridyl or 4(or3)-pyridyl having one or two lower-alkyl substituents.
 7. The compoundaccording to claim 6 where Q is methyl.
 8. The process according toclaim 1 where Q is methyl and the lower-alkylating agent is anethylating agent to produce1-ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid.9. The process according to claim 2 where Q is methyl.
 10. The processaccording to claim 3 where Q is methyl and the lower-alkylating agent isan ethylating agent.
 11. The process consisting of reacting1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-8-oxide with aqueousformaldehyde under alkaline conditions to produce1,4-dihydro-3-hydroxymethyl-7-methyl-4-oxo-1,8-naphthyridine-8-oxide andreacting the latter with an oxidizing agent capable of converting -CH2OHto -COOH to produce3-carboxy-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-8-oxide.
 12. Theprocess consisting of reacting1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-8-oxide with aqueousformaldehyde under alkaline conditions to produce1,4-dihydro-3-hydroxymethyl-7-methyl-4-oxo-1,8-naphthyridine-8-oxide.